Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: an organ culture study

Abstract

BackgroundOnabotulinumtoxin type A (BoNT-A) has been found to reduce pain in chronic migraine. The aim of the present study was to ask if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG) using an organ culture method.MethodsTo induce inflammation, rat TGs were incubated for 24 hrs with either the mitogen MEK1/2 inhibitor U0126, BoNT-A or NaCl. After this the TGs were prepared for immunohistochemistry. Sections of the TG were then incubated with primary antibodies against CGRP (neuronal transmitter), iNOS (inflammatory marker), IL-1β (Interleukin 1β), SNAP-25 (synaptic vesicle docking protein) or SV2-A (Botulinum toxin receptor element).ResultsWe report that CGRP, iNOS, IL-1β, SNAP-25 and SV2-A were observed in fresh TG with a differential distribution. Interestingly, NaCl organ culture of the TG resulted in enhanced expression of CGRP and SNAP-25 in neurons and iNOS in SGCs. Co-incubation with U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1β immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. Moreover, we observed no alteration SV2-A expression in SGCs. Thus, the overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG.ConclusionWe hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs. It is clinically well recognized that treatment with corticosteroids will reduce the symptoms of chronic migraine; however this remedy is associated with long-term side effects. Understanding the mechanisms involved in the expressional alterations may suggest novel ways to modify the changes and indicate novel therapeutics. The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations.

Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets

“…Pilot studies of SPG injection of BoNT-A for treatment of CM as well as in chronic CH (CCH) have showed promising results [22, 23]. A previous study has shown presence of SV-2A and SNAP25 protein with same location in the TG [11]. The present results illustrate a possible site/mechanism of action for BoNT-A in CH.…”

A two years open-label prospective study of OnabotulinumtoxinA 195 U in medication overuse headache: a real-world experience

“…OnabotulinumtoxinA mechanism of action is poorly understood. Recent studies have shown that OnabotulinumtoxinA is able to modulate the inflammatory mediators in the trigeminal ganglion [ 41 ] and decrease interictal CGRP plasma levels in patients with CM [ 42 ], and therefore be effective in the migraine attacks prevention.…”

From transformation to chronification of migraine: pathophysiological and clinical aspects

“…Treatments that have proved efficacy in migraine patients, have been shown to prevent mechanical hyperalgesia in animal models [113,131]. For example, botulinum toxin could act peripherally inhibiting the release of a variety of neurotransmitters which are known to be key signaling molecules in CM including CGRP [132,133], so animal pre-treatment with botulinum toxin can prevent mechanical sensitization inhibiting mechanical nociception in peripheral trigeminovascular neurons [134]. For example, the mechanism of action of noninvasive vagus nerve stimulation for migraine treatment have also been investigated in the inflammatory soup model showing a decrease in periorbital sensitivity after de vagal stimulation [135].…”